PROJECT SUMMARY Background: Tanzania has included SCD as an important public health condition in the country?s non communicable diseases (NCD) strategy. Tanzania ranks 5th, after Nigeria, DRC, India and Angola in countries with the highest numbers of SCD births. Recent estimates show that over 10,000 SCD children under 5 years of age (U5) die annually in Tanzania, representing 6.6% of overall U5 deaths. Developmentally-regulated physiological and pathological changes occur in early childhood that may impact on the natural history of SCD. As hemoglobin ??? globin gene switching occurs; sickle haemoglobin (HbS) gradually replaces fetal haemoglobin (HbF). Disease manifestations, including haemolysis, painful episodes, anaemia, start during this period and continues throughout life. Haemaglobin switching and HbF decline plays a central role in SCD disease expression. The determinants of HbF decline, the spectrum of variation of HbF decline and how these relate to disease expression in the first three years of life is not clear. Specific Aims: (1). To determine the association of HbF decline with SCD clinical expression in the first three years of life (2). To determine the genetic factors associated with HbF decline in babies with and without SCD (3). To study the variation of the pattern and rate of HbF decline in babies with and without SCD. Significance of the study and relevance to public health: The ultimate goal of HbF research is the development of interventions. Understanding the role of HbF decline in SCD disease expression in the early life will inform on the time point for HbF interventions. In addition, elucidating the genetic determinants of HbF decline will highlight the mechanism of HbF switching/ synthesis and hence development of interventions to induce HbF synthesis in adulthood. The unique features and innovation of the project: This study will establish the first SCD birth cohort in Tanzania. The proposed study will follow 400 babies with and without SCD for three years to investigate SCD expression and HbF decline. The methodology: We will use existing newborn screening and immunization platforms to enroll and follow babies from birth up to three years. Gene expression profiling will be used to interrogate genes associated with HbF decline while targeted next generation sequencing will investigate known HbF coding and non coding variants. We will investigate whether genetic factors influence the spectrum of variation of HbF decline and clinical expression. Expected results: To date, there is only one available SCD drug, hydroxyurea, that results in increased HbF levels. Findings from this study will increase knowledge on the opportunities to develop additional interventions as well as better administration of hydroxyurea.